Girdhari Lal

The complement system constitutes a fundamental element of the innate immune response, playing a pivotal role in the identification and eradication of pathogens. The orchestration of complement component activation is closely linked to bone remodeling and the maintenance of skeletal homeostasis. C3a and C5a are notably influential in modulating the differentiation and activity of bone remodeling cells—including osteoclasts, osteoblasts, and osteocytes. Elevated expression or excessive activation of complement components is recognized as a major contributor to bone injury in a variety of inflammatory skeletal disorders. The therapeutic role of complement factors has been evaluated in several models of skeletal diseases. A comprehensive understanding of the complement system in bone remodeling and its therapeutic implications may help in designing innovative strategies to prevent bone degradation and disorders. This review discusses the relationship between the complement system, bone homeostasis, and bone-associated inflammatory diseases. Furthermore, we examine the complement system's potential and its limitations in complement-targeted therapies.

The complement system and natural killer (NK) cells play crucial roles in tumor growth and metastasis. The role of the complement system in affecting the phenotype and anti-tumor function of NK cells remains poorly understood. Using the B16F10 mouse melanoma model, we demonstrated that NK cells from C3−/− mice exhibit increased expression of activation receptors (NKG2D, NKp46, and Ly49H) and reduced inhibitory receptors (NKG2A, Ly49A, and KLRG1) and high cytotoxic activity compared to C3+/+ mice NK cells. C3−/− mice show reduced melanoma tumor growth and metastasis in an NK cell-dependent manner compared to C3+/+ mice. Intratumoral NK cells in C3−/− mice formed a unique phenotypic cluster characterized by higher expression of T-bet, CD69, GITR, CD62L, CCR7, and increased secretion of effector cytokines (IFN-γ, TNF-α, and GM-CSF) and granzyme B expression compared to C3+/+ mice. In C3−/− mice, NK cells from both the spleen and tumors exhibit markedly higher expression levels of C3aR and C5aR1 compared to those from wild-type mice. Activation of C3aR by C3a, leads to phosphorylation of AKT and STAT3 molecules, resulting in phenotypic changes to NK cells. Furthermore, antagonising complement anaphylatoxin receptors C3aR or C5aR1 in wild-type mice resulted in reduced tumor growth, accompanied by an increase in intratumoral effector NK cells. Together, we demonstrated that complement C3 regulates the effector and cytotoxic functions of NK cells, suggesting that targeting complement C3 and the anaphylatoxin receptor may be beneficial in controlling tumor growth in the clinic.

Chemokine CCL20, secreted by gut epithelial cells, demonstrates markedly increased expression during episodes of chronic inflammation and infection. Mucosal barriers recruit more CCR6+ B cells and have higher immunogloblin A (IgA) Ab levels during normal, infectious, and inflammatory states. Ig isotypes at the mucosal surface are pivotal in modulating inflammatory responses and controlling infections. However, the intrinsic signaling pathway mediated by CCR6-CCL20 in B cells—in particular, its impact on Ig isotype expression—remains insufficiently investigated. In this study, the dextran sodium sulfate (DSS)–induced gut inflammation model in C57BL/6 mice was used. Our findings indicate that DSS administration elevates CCL20 production in the gut epithelium, which, in turn, enhances the differentiation of IgA+ B cells in gut-associated lymphoid tissues, while concurrently reducing both IgG1+ B-cell populations and serum IgG1 levels, in a CCR6-dependent manner. Furthermore, stimulation with CCL20 through CCR6 induces phosphorylation of the AKT/mTOR/STAT3 signaling pathways in B cells. Pharmacological inhibition of mTOR signaling with rapamycin effectively abrogated CCL20-driven differentiation of IgA+ B cells. Collectively, these results suggest a significant role for CCR6-CCL20 signaling, alongside other costimulatory mechanisms, in regulating Ig isotype switching at the mucosal barrier during intestinal inflammation, thereby offering important insights into CCR6-mediated inflammatory pathologies.

Bone tissue is comprised of three primary cell types: osteoclasts, the bone resorbing cells; osteoblasts, the bone forming cells; and osteocytes, the cell type involved in mechanotransduction. Osteoclasts are multinucleated cells of hematopoietic origin that degrade bone, while osteoblasts arise from mesenchymal stem cells to synthesize bone matrix. Osteocytes, differentiated from osteoblasts, sense mechanical strain, coordinate with osteoclasts and osteoblasts, and regulate bone remodeling. Cytokines produced during immune responses to infections and autoimmune diseases significantly influence bone homeostasis and metabolism. This review elucidates the roles of both pro- and anti-inflammatory cytokines in bone cell differentiation and function, including their activation of downstream epigenetic and metabolic pathways underlying bone remodeling. Additionally, we discussed how we can exploit these cytokines therapeutically to manage infection or inflammatory diseases related to bone diseases and disorders.

The pathomechanistic role of the complement system is well recognized in various pathological conditions affecting bone tissues and the bone microenvironment, including rheumatoid arthritis, osteoarthritis, bone fractures, and periodontitis. The homeostasis of the bone is maintained by continuous remodeling, in which bone-resorbing or demineralizing osteoclast cells remove bone calcification, and osteoblast cells deposit new bone matrix. Major complement protein C3 is reported to control endochondral ossification, cartilage-to-bone transition, and longitudinal bone growth. The role of the complement protein C3 in differentiating multinucleated osteoclast cells (bone-resorbing cells) from osteoclast precursor cells (OCPs) and its contribution to long bone microarchitecture and strength are unclear. We demonstrated that C3 promotes the differentiation of osteoclasts and the formation of multinucleated osteoclasts from bone marrow–derived OCPs. C3−/− mice OCPs had reduced osteoclast-associated gene expression of TRAP (tartrate-resistant acid phosphatase), cathepsin K, calcitonin receptor, and RANK (receptor activator of nuclear factor κB) molecules compared with osteoclasts derived from wild-type (WT) OCPs. C3−/− mice had significantly increased bone mineral density and other bone parameters of the femur compared with WT mice. Furthermore, compared with WT mice, C3−/− mice were protected from ovariectomy-induced osteoporosis, characterized by significantly increased Foxp3+CD4+ T cells in the spleen and interleukin-10–producing B cells in both the spleen and the bone marrow. Intriguingly, C3 knockout mice exhibit reduced differentiation of functional osteoclast cells, which promotes a strong bone microarchitecture, suggesting that complement pathways may be explored as a therapeutic target in bone inflammatory diseases.

The complement system bridges innate and adaptive immunity, and its role in the tumor microenvironment (TME) is complex and context‐dependent. Multiple recent studies have demonstrated the complement system's pro‐ and anti‐tumor effects. In the present review, we discuss the role of complement in shaping the functions of various immune cells, including T cells, macrophages, natural killer (NK) cells, neutrophils, and dendritic cells within the TME. We also highlighted how complement proteins drive the pro‐ or anti‐inflammatory immune responses, the associated cellular and molecular mechanisms, their influence on anti‐tumor immunity, and some clinical trials targeting complement systems. A comprehensive and critical understanding of the complement system in oncoimmunology may aid in designing effective tumor‐specific therapeutic strategies.

Neuroimmune communication is known to control various regulatory systems in the body. Serotonin (also known as 5-hydroxytryptamine, HT) is one of the neurotransmitters produced predominantly by enterochromaffin cells in the gut and the neurons of the central nervous system. Immune and cancer cells express several HT receptors (HTRs), and how HTRs modulate various immune pathways and contribute to cancer growth and metastasis is unclear. RNA-seq data analysis shows that human colon adenocarcinoma tissues with high HTR _2B expression are associated with poor anti-tumor immune response and poor patient survival. Using an orthotopic mouse model of tumors, we show that HTR _2B and other serotonergic molecule expressions are positively associated with colon tumor progression. Antagonizing the HTR _2B using specific chemical antagonists significantly suppresses the progression of colon, breast, and melanoma tumors and metastasis in mice by promoting antigen-specific cytotoxic CD8 T cell response and downregulating the PD-L1 expression on tumor cells. Further, treatment with a combination of suboptimal doses of HTR _2B antagonists and suboptimal doses of immunotherapy (anti-PD1, anti-PD-L1, or anti-CTLA4 mAb) or chemotherapeutic drugs (5-fluorouracil, oxaliplatin, or irinotecan) showed a robust anti-tumor response and inhibited colon tumor growth. Our finding showed that antagonizing the HTR _2B holds a potent therapeutic advantage as a combinatorial regimen of either immunotherapy or chemotherapy to treat colon cancer. One sentence summary: HTR _2B expression is associated with colon tumor progression, and antagonizing the HTR _2B inhibits tumor growth and metastasis.